Hyaluronic acid is a polysaccharide whose chain is constituted by alternating units of 1,4-.beta.-D-glucuronic acid and 1,3-.beta.-N-acetyl-D-glucosamine. Hyaluronic acid is a fundamental component of connective tissue of animals, being present, for example, in the skin and cartilage. It is also found in high concentrations in the umbilical cord, in the synovial fluid and vitreous humor of the eye. Currently, the preferred source of hyaluronic acid is by extraction from cockscombs, even though the production of hyaluronic acid from Streptococcus cultures is becoming increasingly widespread (T. J. Lieselang. Survey of Ophthalmology 34,268-293, 1990).
As hyaluronic acid is a fundamental component of the connective tissue, it is biocompatible, bioadsorbable and not immunogenic. It therefore plays a key role in many biological functions, such as tissue hydration, the organization of proteoglycans in the cartilage, tissue repair, embryonic development and lubrication and protection of joint cartilage. This polysaccharide is commonly used in the treatment of some joint diseases, such as rheumatoid arthritis. It is also used in what is known as microviscosurgery, and in particular, in surgery to the eye. In this application, the biocompatibility and rheological characteristics of concentrated solutions of high-molecular-weight hyaluronic acid are exploited.
In cases of inflammation of the joints, hyaluronic acid is degraded by superoxide radicals (Greenwald R. A. et al., Inflammation, 10, 15-30, 1986). This degradation determines a notable reduction in the rheological and viscoelastic characteristics of the synovial fluid, markedly reducing the lubricant and protective effect which hyaluronic acid has on the cartilage. It has been hypothesized that the superoxide dismutase enzyme constitutes the main defense against damage caused by the superoxide radical which is produced in the course of inflammatory processes. Copper and zinc are components of the superoxide dismutase enzyme, the function of which seems to be to protect cells from the toxic effects of endogenous superoxide radicals.
Rheumatoid arthritis has been associated with zinc deficiencies and an antiinflammatory activity has been hypothesized for zinc itself (A. Frigo et al., "Copper and Zinc in Inflammation", Inflammation and drug therapy series, Vol. IV, Kluwer Academic Publishers, pp. 133-142, 1989). Treatment with zinc sulfate has proved to be efficacious in controlling joint disorders caused by arthritis in patients affected by psoriasis.
In the same way, alterations in copper concentrations have been observed in patients affected by inflammatory diseases in the joints (C. W. Denko, "Copper and Zinc in Inflammation, Inflammation and drug therapy series, Vol. IV, Kluwer Academic Publishers, pp. 1-5, 1989). Copper-based compounds have been used to treat rheumatoid arthritis and their activity is attributed to copper ions.
Gold salts are also used as drugs to treat arthritis, together with known antiinflammatory products of a steroid and non-steroid type (U.S. Pat. No. 4,746,504).
Many silver salts, such as silver fluoride, silver iodide, silver lactate, have been used as antibacterial agents for topical use. Their antimicrobial activity is due to the action of the Ag+ ions.
Heavy metal salts of hyaluronic acid are therefore already known to the state of the art, such as silver, gold, cerium and tungsten. The reaction between a sodium hyaluronate aqueous solution and a silver nitrate solution gives the silver salt of hyaluronic acid. Pharmaceutical preparations containing all these compounds are used to advantage for the treatment of burns, wounds and some ophthalmic infections such as gonococcus-induced conjunctivitis (A. Nimrod and B. Greenman, U.S. Pat. No. 4,746,504, May 24, 1988).
However, neither hyaluronic acid nor hyaluronic acid partial or total ester derivatives wherein one or more hydroxy functions of its 1,4.beta.-D-glucuronic acid and 1,3-.beta.-N-acetyl-D-glucosamine alternating repeating units esterified with a carboxyl group of succinic acid to form the succinic hemiester of hyaluronic acid or hyaluronic acid total or partial esters are known to the state of the art.